Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients1 2

Thervet, Éric; Anglicheau, Dany; King, Barry P; Schlageter, Marie‐Hélène; Cassinat, Bruno; Beaune, Philippe; Legendre, Christophe; Daly, Ann K.

doi:10.1097/01.tp.0000090753.99170.89

Cited by 273 publications

(196 citation statements)

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“…Subjects homozygous for the variant * 3, likely owing to the lower metabolic drug clearance, require a lower tacrolimus dose to reach the desired therapeutic levels compared to the subjects with at least one * 1 copy who are considered to express the functional enzyme (21,40,41). Similar results have been previously reported for liver (8,(41)(42)(43), kidney (12,(44)(45)(46)(47), heart (48), and lung recipients (49). In particular, as regards to liver transplantation, our data support the primary importance of the donor with respect to the CYP3A5 genotype (8,43,(50)(51)(52)(53); however, they suggest a possible influence of the recipient genotype also (52), which might be corroborated by the known metabolic role of CYP3A5 in extra-hepatic tissues such as the intestine (51,53).…”

Section: Treated With Steroidssupporting

confidence: 81%

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

et al. 2011

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Abstract. Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C 0 ) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5 For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C 0 levels were significantly lower in patients with one copy of the * 1 allele compared to those homozygous for the * 3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.

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Section: Treated With Steroidssupporting

confidence: 81%

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

et al. 2011

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“…However, in renal transplant patients, the in vivo clearance of both tacrolimus and sirolimus is dependent on CYP 3A5 polymorphism: it was demonstrated that patients with the CYP 3A5*3/*3 genotype had significantly lower tacrolimus dose-adjusted trough level than CYP 3A5*1 allele carriers (Hesselink et al, 2003;Thervet et al, 2003). Anglicheau et al (2005) found a significant association between the CYP 3A5*3 single nucleotide polymorphism and sirolimus doseadjusted trough levels in 69 patients under a sirolimus-based rescue therapy, but not in 51 de novo patients or in 29 patients coadministered cyclosporine or tacrolimus (Anglicheau et al, 2005).…”

Section: Metabolism Of Sirolimus By Cyp 3a4 and Cyp 3a5mentioning

confidence: 99%

Metabolism of Sirolimus in the Presence or Absence of Cyclosporine by Genotyped Human Liver Microsomes and Recombinant Cytochromes P450 3A4 and 3A5

Picard¹,

Djebli²,

Sauvage³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Sirolimus is an immunosuppressive drug currently used alone or in combination with cyclosporine. Both drugs undergo extensive metabolism by the CYP 3A enzymes. This study aimed at comparing the activity of recombinant CYP (rCYP) 3A4 and 3A5 toward sirolimus, investigating the effect of cyclosporine on the metabolic rate of these two cytochromes P450 (P450s), as well as the impact of the CYP 3A5*3 polymorphism on that of human liver microsomes (HLMs). Two distinct approaches were used; i.e., the measurement of (1) hydroxy-sirolimus and desmethyl-sirolimus production, and (2) sirolimus depletion by the in vitro half-life method. rCYP 3A5 exhibited a lower intrinsic clearance (CL int ) for both hydroxylation (0.11 versus 0.24 l/pmol P450/min) and depletion of sirolimus (0.64 versus 2.36 l/pmol P450/min) than rCYP 3A4. Similar CL int values for hydroxylation, demethylation, and depletion were found when comparing a pool of HLMs carrying at least one CYP 3A5*1 (active) allele with a pool of HLMs not expressing CYP 3A5. This was further confirmed for sirolimus depletion using individual microsome preparations (p ‫؍‬ 0.42). A deeper inhibitory effect of cyclosporine on the CL int of sirolimus depletion was found for rCYP 3A4 than for rCYP 3A5 (i.e., ؊44% versus ؊8% at 0.62 M, 750 g/l cyclosporine), and sirolimus metabolism was slightly less inhibited for HLMs expressing CYP 3A5 than not (؊38% versus ؊56%). In the absence of cyclosporine, the CYP 3A5*3 polymorphism may not influence significantly sirolimus metabolism at the hepatic level. However, strong CYP 3A4 inhibition by cyclosporine could unveil the influence of this polymorphism.

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“…Such results have been reported previously in the literature concerning this polymorphism. [5][6][7][8][9][10] A previous study by Patel and associates studied the effect of CYP3A5 polymorphism on tacrolimus drug dosing in North Indian renal allograft recipients. 11 To our knowledge, the present study is the first study to show the association between CYP3A5 genetic polymorphism and tacrolimus drug level in a South Indian population.…”

Section: Discussionmentioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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Objectives: Tacrolimus is the cornerstone for immunosuppression in renal transplant and is metabolized by the cytochrome P 450 3A (CYP3A) subfamily of enzymes in the liver and small intestine. A polymorphism in intron 3 of the CYP3A5 gene affects the expression of this enzyme and tacrolimus trough blood levels. The purpose of this study was to identify the proportion of CYP3A5 gene polymorphisms in South Indian renal transplant patients and determine the effect of CYP3A5 gene polymorphisms on tacrolimus trough blood levels in patients with and without CYP3A5 expression. Materials and Methods:We included 25 adult patients who underwent renal transplant at Government Medical College, Trivandrum. All patients received tacrolimus (dose, 0.1 mg/kg/body weight, in 2 divided doses). Tacrolimus trough blood levels were determined on postoperative day 6. The CYP3A5 genotype analysis was performed by polymerase chain reaction amplification of target and detection by restriction fragment length polymorphism analysis. Results: The CYP3A5*1/*1 genotype was detected in 5 recipients (20%), *1/*3 genotype in 5 recipients (20%), and *3/*3 genotypes in 15 recipients (60%) of the total 25 graft recipients.Mean tacrolimus level in the CYP3A5*1/*1 group was 5.154 ng/mL (range, 4.42 to 6.5 ng/mL), CYP3A5*1/*3 group was 5.348 ng/mL (range, 3.1 to 9.87 ng/mL), and CYP3A5*3/*3 group was 9.483 ng/mL (range, 4.5 to14.1 ng/mL). Acute rejection episodes were significantly more frequent for CYP3A5*1/*1 homozygous patients (40%) than patients with CYP3A5*1/*3 (20%) or CYP3A5*3/*3 (13%) genotypes. Conclusions: Most patients carried the mutant allele CYP3A5*3 (A6986G). Tacrolimus drug level correlated well with presence or absence of CYP3A5 polymorphisms. Acute rejection episodes were more frequent in expressors, and they may require higher doses of tacrolimus. Similarly, tacrolimus nephrotoxicity was more frequent in nonexpressors. Therefore, CYP3A5 polymorphism analysis before renal transplant may help determine the optimal dose of tacrolimus in this population and prevent acute rejection episodes or tacrolimus toxicity.

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Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients1 2

Abstract: Determination of CYP3A5 genotype is predictive of the dose of tacrolimus in renal transplant recipients and may help to determine the initial daily dose needed by individual patients for adequate immunosuppression without excess nephrotoxicity.

Cited by 273 publications

References 10 publications

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Metabolism of Sirolimus in the Presence or Absence of Cyclosporine by Genotyped Human Liver Microsomes and Recombinant Cytochromes P450 3A4 and 3A5

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